Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

Acute lung injury due to alpha-naphthylthiourea (ANTU) is associated with increased permeability edema, transient pulmonary hypertension, and increased vascular reactivity. We sought to determine whether repeated administration of ANTU caused right ventricular hypertrophy. Rats were injected weekly for 4 wk with ANTU or an equivalent volume of the vehicle Tween 80. Rats injected repeatedly with ANTU in doses of 5–10 mg/kg body wt had increased ratios of right ventricular to left ventricular plus septal weights. The right ventricular hypertrophy in ANTU-treated rats was associated with right ventricular systolic hypertension. Repeated injections of ANTU also caused transient pulmonary edema after each dose, as evidenced by increased wet-to-dry lung weight ratios after 4 h, which returned to normal by 24 h. Lungs isolated from ANTU-injected rats had greater pressor responses to hypoxia and to angiotensin II than lungs from Tween 80-injected rats. Pressure-flow curves of isolated lungs, arterial blood gases, and hematocrits were similar in rats treated repetitively with ANTU or Tween alone. Lung histology was also similar in ANTU and control lungs, as were measurements of arterial medial thickness and ratios of numbers of arteries/100 alveoli, indicating that substantial vascular remodeling had not occurred. Thus, four weekly ANTU injections in rats caused right ventricular hypertrophy, probably due to pulmonary hypertension. We speculate that the pulmonary hypertension was due, at least in part, to sustained vasoconstriction, which somehow resulted from repeated acute lung injury.

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Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00389.2014 ◽

2015 ◽

Vol 309 (3) ◽

pp. L262-L270 ◽

Cited By ~ 18

Author(s):

Xueyu Chen ◽

Frans J. Walther ◽

Rozemarijn M. A. Sengers ◽

El Houari Laghmani ◽

Asma Salam ◽

...

Keyword(s):

Right Ventricular ◽

Ventricular Hypertrophy ◽

Pulmonary Inflammation ◽

Right Ventricular Hypertrophy ◽

Control Treatment ◽

Wall Thickening ◽

Continuous Exposure ◽

Neonatal Rats ◽

Alveolar Development ◽

Collagen Iii

Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.

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Effects of thrombocytopenia on monocrotaline pyrrole-induced pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1984.246.6.h747 ◽

1984 ◽

Vol 246 (6) ◽

pp. H747-H753 ◽

Cited By ~ 2

Author(s):

K. S. Hilliker ◽

T. G. Bell ◽

D. Lorimer ◽

R. A. Roth

Keyword(s):

Pulmonary Hypertension ◽

Lung Injury ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Blood Platelet ◽

Lavage Fluid ◽

Right Ventricular Hypertrophy ◽

Lactate Dehydrogenase Activity ◽

Hypertrophic Response ◽

Monocrotaline Pyrrole

Monocrotaline pyrrole (MCTP) causes lung injury, pulmonary hypertension, and right ventricular hypertrophy in rats. To determine if platelets are involved in the cardiopulmonary effects of MCTP, the response to MCTP was determined in thrombocytopenic rats. Blood platelet count was reduced to 10–20% of normal for 48 h by ip administration of an antirat platelet serum (PAS) prepared in the goat. Rats were treated iv with either MCTP 5 mg/kg or dimethylformamide vehicle and with either PAS or preimmune serum. Fourteen days after MCTP, right ventricular hypertrophy and several indexes of lung injury were measured. MCTP treatment produced right ventricular hypertrophy, increased lactate dehydrogenase activity and protein concentration in bronchopulmonary lavage fluid, increased perfusion pressure in isolated lungs, and decreased pulmonary clearance and metabolism of perfused 5-hydroxytryptamine. Thrombocytopenia did not influence the changes in these indexes of lung injury produced by MCTP in this protocol. When PAS was given 12 h before MCTP, it did not affect right ventricular hypertrophy, but when PAS treatment was begun 3 or 6 days after MCTP, right ventricular hypertrophy was decreased by 19 or 41%, respectively. These results suggest that platelets help to mediate the development of pulmonary hypertension and the hypertrophic response of the right heart following MCTP administration.

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Collagen metabolism during right ventricular hypertrophy following induced lung injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.251.5.h915 ◽

1986 ◽

Vol 251 (5) ◽

pp. H915-H919 ◽

Cited By ~ 1

Author(s):

J. E. Turner ◽

M. H. Oliver ◽

D. Guerreiro ◽

G. J. Laurent

Keyword(s):

Lung Injury ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Collagen Synthesis ◽

Heart Tissue ◽

Right Ventricular Hypertrophy ◽

Collagen Content ◽

Degradation Rates ◽

The Right ◽

Tissue Matrix

Collagen synthesis and degradation rates were estimated in ventricles of normal rabbits and in those with right ventricular hypertrophy resulting from bleomycin-induced lung injury. Synthesis rates were estimated from the radioactivity in tissue [14C]hydroxyproline following a single intravenous injection of [14C]proline with a "flooding" dose of unlabeled proline (Biochem. J. 206: 535-544, 1982). The rate in the left ventricle was 5.8 +/- 1.0 compared with 2.9 +/- 0.4%/day in the right (P less than 0.02). Degradation rates, based on [14C]hydroxyproline levels in the tissue-free pool, indicated that in both normal ventricles about one-third of newly produced collagen was degraded rapidly following its synthesis. Six days after bleomycin, right ventricular collagen content fell by 35%, associated with a marked increase in tissue-free hydroxyproline levels. After 14 days the right ventricular weight and collagen content had increased by 49.4 +/- 3.7% (P less than 0.001) and 31.7 +/- 4.4% (P less than 0.05), respectively, and collagen synthesis rates increased to 9.7 +/- 1.8%/day (P less than 0.001). It is concluded that collagen is synthesized and degraded quite rapidly in normal heart tissue but that fractional rates differ between ventricles. The evidence also suggests that increased collagen synthesis and breakdown of mature collagen occurs as the connective tissue matrix is remodeled during adaptive cardiac growth.

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PAF antagonists inhibit monocrotaline-induced lung injury and pulmonary hypertension

Journal of Applied Physiology ◽

10.1152/jappl.1991.71.6.2483 ◽

1991 ◽

Vol 71 (6) ◽

pp. 2483-2492 ◽

Cited By ~ 34

Author(s):

S. Ono ◽

N. F. Voelkel

Keyword(s):

Pulmonary Hypertension ◽

Lung Injury ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Platelet Activating Factor ◽

Lipid Mediators ◽

Right Ventricular Hypertrophy ◽

Vascular Leak ◽

Paf Antagonists ◽

Web 2086

Lung platelet-activating factor (PAF) levels increased in some rats at 1–3 wk after subcutaneous injection of monocrotaline (MCT). We tested the effect of specific PAF antagonists, WEB 2086 and WEB 2170, on MCT-induced lung injury and subsequent pulmonary hypertension and right ventricular hypertrophy. Treatment with either agent decreased MCT-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk after injection. Treatment with WEB 2170 reduced MCT-induced pulmonary vascular leak at 1 wk after injection, and WEB 2086-treatment exclusively during the early leak phase also decreased MCT-induced right ventricular hypertrophy at 3 wk. Treatment with WEB 2170 between the 3rd and 4th wk after MCT injection inhibited the progression of right ventricular hypertrophy at 4 wk. These results suggest that PAF contributes to the early pulmonary vascular leak, and this leak phase is important for the development of pulmonary hypertension and right ventricular hypertrophy in MCT-treated rats. Furthermore, it appears that PAF action contributes to the maintenance of a chronic inflammatory process that involves the synthesis of other lipid mediators (prostaglandins and leukotrienes) and leads to pulmonary hypertension. We conclude that PAF has a role in the MCT-induced inflammatory lung injury and pulmonary hypertension.

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Apelin Attenuates Pulmonary Inflammation and Fibrin Deposition in Neonatal Hyperoxic Lung Injury.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2212 ◽

2009 ◽

Cited By ~ 3

Author(s):

YP de Visser ◽

FJ Walther ◽

EH Laghmani ◽

A van der Laarse ◽

GT Wagenaar

Keyword(s):

Lung Injury ◽

Pulmonary Inflammation ◽

Fibrin Deposition ◽

Hyperoxic Lung Injury

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Neither anticoagulant nor nonanticoagulant heparin affects monocrotaline lung injury

Journal of Applied Physiology ◽

10.1152/jappl.1987.62.2.816 ◽

1987 ◽

Vol 62 (2) ◽

pp. 816-820 ◽

Cited By ~ 5

Author(s):

J. W. Fasules ◽

K. R. Stenmark ◽

P. M. Henson ◽

N. F. Voelkel ◽

J. T. Reeves

Keyword(s):

Pulmonary Hypertension ◽

Lung Injury ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Right Ventricular Hypertrophy ◽

Vascular Leak ◽

Hypoxic Pulmonary Hypertension ◽

Antiproliferative Agent ◽

The Right ◽

Insight Into

The administration of monocrotaline to rats causes pulmonary vascular leak within 1 wk followed in 2–3 wk by perivascular proliferation and fatal pulmonary hypertension. Possibly blocking the proliferation might block the pulmonary hypertension, providing insight into its mechanism. Because heparin, given as an antiproliferative agent, reduced hypoxic pulmonary hypertension in mice, it might also block monocrotaline-induced pulmonary hypertension. Alternatively, anticoagulation could worsen the lung injury. We found that heparin (300 and 600 U/kg sc twice daily) inhibited clotting in rats given monocrotaline but did not change the vascular leak, the right ventricular pressure, the right ventricular hypertrophy, the increased medial thickness of the pulmonary arterioles, or the production of a slow-reacting substance of anaphylaxis-like material by the lungs. A nonanticoagulant heparin fragment (2 mg/kg sc twice daily), given to avoid anticoagulation also did not influence the monocrotaline injury. Thus neither anticoagulant nor nonanticoagulant heparin either attenuated or worsened the measured effects of monocrotaline.

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